Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often selected as a curative treatment strategy for acute myeloid leukemia (AML). In particular, AML patients with poor cytogenetics at diagnosis are considered for allo-HSCT as the first-line therapy.1, 2, 3 Recently, we have reported that AML with the t(6;9)(p23;q34) abnormality, which predicts a very poor prognosis in patients treated with chemotherapy,4 is associated with an outcome in patients receiving allo-HSCT that is comparable to that in patients with a normal karyotype.5 However, 55% of the AML patients with t(6;9)(p23;q34) eventually had a negative outcome. We herein performed a further analysis for AML patients with t(6;9)(p23;q34) who received allo-HSCT to identify the prognostic factors affecting their overall survival (OS).
A total of 64 de novo AML patients with t(6;9)(p23;q34) detected in G-band staining at diagnosis, who received their first allo-HSCT between January 1996 and December 2007, were extracted from the databases of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the Japan Cord Blood Bank Network. The cytogenetic data were analyzed according to the Southwestern Oncology Group criteria for each institution, instead of by central review.2 The clinical data were collected using a standardized report form, which was submitted at 100 days, 1 year and annually after HSCT. This study was approved by the Committee for Nationwide Survey Data Management of the JSHCT. Written informed consent was obtained in accordance with the Declaration of Helsinki. The OS was defined as the number of days from HSCT until death from any cause. Non-relapse mortality (NRM) was defined as death without relapse. Any patients who were alive at the last-follow-up date were censored. The analysis was performed using the R version 2.13.0 software program (R Foundation for Statistical Computing; www.r-project.org).6 The probability of OS was calculated using the Kaplan–Meier method and compared using the log-rank test. The probabilities of transplant related mortality and disease relapse were compared using the Grey test7 and were analyzed using the cumulative incidence analysis,6 while considering relapse and death without disease relapse as respective competing risks. The following variables related to the survival of the adult patients older than 15 years and their clinical data were compared in a univariate analysis: recipient characteristics (age; younger than 35 vs. older than 35 years, gender, performance status at diagnosis; 0 to 2 vs. 3 or 4, FAB classification; M2 or others, positivity for peroxidase in leukemic blasts at diagnosis; less than 50% vs. greater than 50%, cytogenetic abnormality), donor characteristics (age; younger than 35 vs. older than 35 years, gender, sex compatibility, compatibility of cytomegalovirus antibody serostatus, relationship; related vs. unrelated, and ABO compatibility), transplant characteristics (disease status at HSCT; complete remission (CR) vs. non-CR, use of total body irradiation as a preconditioning regimen, source of the graft; bone marrow, peripheral blood stem cell, cord blood (CB)), graft-versus-host disease prophylaxis; cyclosporine versus tacrolimus and the use of methotrexate. Multivariate Cox models were used to evaluate the hazard ratios associated with the prognosis. Covariates found to be significant in the univariate analyses (P⩽0.10) were included in the models. For both the univariate and the multivariate analyses, P-values were two sided, and outcomes were considered to be significant for P⩽0.05.
The characteristics of the 64 AML patients with t(6;9)(p23;q34) were shown in Table 1a. The OS of the seven pediatric patients younger than 14 years old seemed to be better than the OS of the 57 adult patients older than 15 years, although there were no statistically significant differences between the groups (Figure 1a, the probability of 3-year OS in pediatric patients and adult patients was 83% and 48%, respectively (P=0.12)). We performed a further analysis in the 57 adult patients older than 15 years. The univariate analysis showed that the disease status at HSCT was the sole significant prognostic factor affecting the OS (Figure 1b, the probability of 3-year OS in patients with CR and with non-CR at HSCT was 69% and 29%, respectively (P<0.003)), and the number of HLA disparities, M2 in the FAB classification and CB as the source of the graft were calculated to have a P-value <0.1 (Table 1b). No statistically significant tendencies related to gender, gender mismatch between the donor and recipient, recipient cytomegalovirus serostatus or the use of total body irradiation for the preconditioning regimen were observed. The cumulative incidence of relapse and of NRM are shown in Figure 1c; the cumulative incidence of relapse was significantly lower in patients with a CR at HSCT than in patients without CR, although such differences were not seen in the cumulative incidence of NRM between these two groups (the 3-year cumulative incidence of relapse was 25% in CR patients and 58% in non-CR patients (P=0.005), and the 3-year cumulative incidence of NRM was 10% in CR patients and 16% in non-CR patients (P=0.85)). In the multivariate analysis, the disease status at HSCT and FAB-M2 remained the significant variables associated with the OS (Table 1b). The OS of the patients categorized by the combination of the disease status at HSCT and FAB-M2 showed a favorable outcome in FAB-M2 patients with a CR at HSCT (Figure 1d, the probability of 3-year OS in patients with CR/FAB-M2, CR/non-FAB-M2, non-CR/FAB-M2 and non-CR/non-FAB-M2 was 76%, 60%, 43% and not reached, respectively (P<0.001)). In contrast, the patients who were not in remission at the time of HSCT and had non-FAB-M2 showed a poorer outcome; the cause of death in six out of the nine patients was due to a relapse of the AML.
The characteristics of the patients with the t(6;9)(p23;q34) subtype of AML were known to have a poor prognosis and to be associated with development at a younger age, frequent M2 in the FAB classification and achievement of a morphological first CR not predicting a favorable outcome.8 In this study, we distinguished the seven pediatric patients who seemed to have a superior OS from the adult patients, because the better prognosis in the children might reflect differences in the pathogenesis of the disease, consistent with the better OS in the previous report.4 The current study revealed that the cumulative incidence of relapse was significantly worse in patients without CR than in patients with CR, although the cumulative incidence of NRM was comparable between these two groups. These results indicate that it is important to have an appropriate treatment strategy, that is, allo-HSCT for the patients who achieved first CR is imperative, while the development of an effective treatment for the refractory/relapsed AML patients is critical. The presence of FLT3-ITD is recognized as a poor prognostic factor in AML patients.9 As FLT3-ITD was frequently detected in patients with t(6;9)(p23;q34),4 it has been suggested that the presence of FLT3-ITD might contribute to the poor prognosis of the t(6;9)(p23;q34) patients.10 With regard to the rate of FLT3-ITD–positive disease, there was no apparent between-group differences in the FAB classification;11 however, the expression levels of FLT3 were higher in patients with monocytic AML (M4 and M5 in the FAB classification) than in the other patients,12 and were associated with an unfavorable prognosis.13 The current study has distinguished FAB-M2 from non-M2, and two-thirds of the non-M2 cases (n=23) in this study consisted of monocytic AML (the number of M4 patients and M5 patients was 13 and 2, respectively). Therefore, the poor prognosis of the non-FAB-M2 patients might be due to the presence of FLT3-ITD. Unfortunately, we could not confirm this hypothesis because this retrospective analysis did not examine the presence of FLT3-ITD. Future studies will be needed to determine whether the FLT3-ITD status was responsible for the poor prognosis in these patients.
In conclusion, this study showed that a CR at the time of HSCT and M2 in the FAB classification are favorable prognostic factors in AML patients with t(6;9)(p23;q34). However, refractoriness to chemotherapy remains an obstacle to a favorable allo-HSCT outcome, especially in non-M2 patients. Novel therapeutic approaches, such as immunotherapy using anti-FLT antibodies combined with HSCT, may also be required for patients expected to have a poor prognosis.14, 15
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We are indebted to all of the patients and the staff of the participating institutions of the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, The Japanese Cord Blood Bank Network and The Japanese Society of Pediatric Hematology. We also thank Ms Takako Sakai, data manager of the Japan Society for Hematopoietic Cell Transplantation Data Registry, for their excellent assistance.
The authors declare no conflict of interest.
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Ishiyama, K., Takami, A., Kanda, Y. et al. Prognostic factors for acute myeloid leukemia patients with t(6;9)(p23;q34) who underwent an allogeneic hematopoietic stem cell transplant. Leukemia 26, 1416–1419 (2012) doi:10.1038/leu.2011.350
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